Reductive opening of a cyclopropane ring in the Ni(II) coordination environment: a route to functionalized dehydroalanine and cysteine derivatives

The involvement of an α,α-cyclopropanated amino acid in the chiral Ni(II) coordination environment in the form of a Schiff base is considered as a route to electrochemical broadening of the donor–acceptor cyclopropane concept in combination with chirality induction in the targeted products. A tendency to the reductive ring-opening and the follow-up reaction paths of thus formed radical anions influenced by substituents in the cyclopropane ring are discussed. Optimization of the reaction conditions opens a route to the non-proteinogenic amino acid derivatives containing an α–β or β–γ double C=C bond in the side chain; the regioselectivity can be tuned by the addition of Lewis acids. One-pot combination of the reductive ring opening and subsequent addition of thiols allows obtaining the cysteine derivatives in practical yields and with high stereoselectivity at the removed β-stereocenter.

Experimental details 1 H (400.0 MHz) and 13 C (100.6 MHz) NMR spectra (including COSY, HMBC, HSQC) were recorded using an Aglient 400-MR spectrometer in CDCl3. Chemical shifts were referenced to the nondeuterated aliquot of the solvent.
Mass spectra. CH3CN (LC-MS grade) for ESI-MS experiments was ordered from Merck and used as received. Sodium formate (for HPLC) for calibration was ordered from Sigma-Aldrich. The samples for ESI-MS experiments were prepared in 1.8 mL glass vials/screw top caps with PTFE septa for HPLC experiments (Agilent Technologies).
Preparative electrolysis was performed with AutoLab PGSTAT100N potentiostat in a twocompartment cell of 10 mL volume. The WE was glassy carbon plate (300 mm 2 ); the CE was a stainless steel wire. The solution was stirred with an argon flow. Optical rotations were measured on a Krüss P8000 polarimeter.

Synthesis of complex 4
Synthesis was performed in an argon atmosphere using the standard Schlenk technique. The solution of Δ-AlaNi (1.142 g, 2.24 mmol) in toluene (10 mL) was degassed, then BrCH(COOMe)2 (709 mg, 3.36 mmol, 1.5 equiv) was added. After 5 minutes NaH (136 mg, 3.4 mmol, 60% suspension in a mineral oil) was added. The reaction mixture was stirred at room temperature for 30 min. Afterwards, the reaction mixture was poured onto water; organic compounds were extracted with ethyl acetate. The combined organic fractions were dried over anhydrous Na2SO4; the solvent was evaporated under reduced pressure. The residue was separated using column chromatography. The first fraction was eluted with a CHCl3/AcMe = 10:1 (the minor isomer); the second (major) fraction corresponding to the (S)-isomer was eluted with a CHCl3/AcMe = 1:1 mixture). After removal of the solvent, (R)-4 (49 mg, 3.5%) and (S)-4 (1.17 g, 82%) were obtained.

Reductive ring opening of complex 4
Solution of Bu4NBF4 (10 mL 0.09 M) in DMF was placed into the two-compartment electrochemical cell equipped with the magnetic stirrer. In the working electrode compartment, S5 complex 4 (50 mg, 0.078 mmol) and azobenzene (method A: no azobenzene; method B: 15 mg (0.082 mmol)) were added. Potentiostatic electrolysis (E = −1.70 V (method A), E = −1.50 V (method B) vs Ag/AgCl, KCl(sat.)) of the solution deaerated with an argon flow was performed using a carbon felt as a working electrode and a Fe-rod as a counter electrode. The color of the solution was changed from red to dark purple during the electrolysis. After a charge of 7.5 C (1 F/mol of complex 4, method A) or 18 C (2.4 F/mol of complex 4, method B) was passed through the solution, PhNEt2·HCl (31 mg, 0.167 mmol) was added. After 5 minutes the solution from the working electrode compartment was poured onto water (15 mL) and extracted with ethyl acetate (3 × 15 mL). Organic fractions were washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified using column chromatography (hexane/acetone = 1:1). After evaporation of the solvent and drying in vacuum the following complexes were isolated: Method A: complexes 6 (20 mg, 40%), complex 7 (20 mg, 40%).

Reductive ring opening followed by the reaction with electrophiles (AcOH or MeI)
Solution of Bu4NBF4 (10 mL 0.09 M) in DMF was placed into the two-compartment electrochemical cell equipped with the magnetic stirrer. In the working electrode compartment, complex 3 (60 mg, 0.1 mmol) was added. Potentiostatic electrolysis (E = −1.70 V vs Ag/AgCl, KCl(sat.)) of the solution deaerated with an argon flow was performed using a carbon felt as a working electrode and a Fe-rod as a counter electrode. The color of the solution was changed from red to dark purple during the electrolysis. After a charge of 10 C (1 F/mol of complex 3) was passed through the solution, 1 mL of DMF containing acetic acid (13 μl, 0.2 mmol) or MeI (64 μl, 1 mmol) was added to the reaction mixture. Then the reaction mixture was poured onto water (15 mL) and extracted with ethyl acetate (3 х 15 mL). Organic fractions were washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was separated with column chromatography, using the following eluents: CHCl3/AcMe = 5:1 (in the experiment with AcOH as an electrophilic additive), CCl4/iPrOH = 10:1 (in the experiment with MeI addition). After evaporation of the solvent and drying in vacuum the following complexes were isolated: After protonation: complex 8 (10 mg, 20%), complex 5 as a single diastereomer 1 (10 mg, 20%).

One-pot electrosynthesis of cysteine derivatives from complex 4
Solution of Bu4NBF4 (10 mL 0.09 M) in DMF was placed into the two-compartment electrochemical cell equipped with the magnetic stirrer. In the working electrode compartment, complex 4 (50 mg, 0.078 mmol) and azobenzene (15 mg, 0.082 mmol) were added. Potentiostatic electrolysis (E = −1.50 V vs Ag/AgCl, KCl(sat.)) of solution deaerated with an argon flow was performed using carbon felt as a working electrode and Fe-rod as a counter electrode. The color of the solution during the electrolysis changed from red to dark purple. After a charge of 18 C (2.4 F/mol of complex 4) was passed through the solution, PhNEt2·HCl (31 mg, 0.167 mmol) was added. After 5 min of intensive stirring, RSH (0.16 mmol) and Et3N (method B) were added (method A: no Et3N; method B: 7.26 mg, 0.07 mmol of Et3N). The solution from the working electrode compartment was transferred to the Schlenk tube preliminary charged with argon and kept at room temperature for 24 h. Then the reaction mixture was poured onto water (15 mL) and extracted with ethyl acetate (3 × 15 mL). Organic fractions were washed with brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was separated using column chromatography (Silicagel, CHCl3/AcMe = 15:1 mixture was used as an eluent; for further purification of each diastereomer hexane/AcOEt = 1:5 mixture was used). After evaporation of the solvent and drying in vacuum the following complexes were obtained: Method A: TolSH: complex 10 (32 mg, 54%, (R,S)/(R,R)=1:5), complexes 6 (20 mg (40%)).